Prediction of adipose tissue: Plasma partition coefficients for structurally unrelated drugs

Poulin, Patrick; Schoenlein, Kerstin; Theil, Frank‐Peter

doi:10.1002/1520-6017(200104)90:4<436::aid-jps1002>3.0.co;2-p

Cited by 192 publications

(158 citation statements)

References 41 publications

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“…The choice of sub-compartments is motivated by the availability of physiological data and for pharmacokinetic and pharmacodynamic reasons (11,19,20). For the generic parameterization, drug exchange by passive diffusion, non-saturable distribution processes and the absence of metabolic processes is assumed, as in existing models for predicting tissue partition coefficients (12)(13)(14)16). Extensions are discussed.…”

Section: Sub-compartment Tissue Distributionmentioning

confidence: 99%

“…To recognize this and to find appropriate experimental realizations was the break-through in a priori determination of partition coefficients (13,14). The differences between existing tissue distribution models regard (i) the tissue constituents that are taken into account and (ii) the approximation of partition coefficients for the resulting constituents by in vitro data.…”

Section: Sub-compartment Tissue Distributionmentioning

confidence: 99%

“…Parameter values can be found in (16,26) for the species rat. In their seminal papers in 2000/01 (13,14), Poulin and Theil proposed an in silico approach to a priori predict tissue-plasma partition coefficients solely based on few compound specific in vitro data. They assumed that the compound is present in dissolved form in tissue water, that it may bind to macromolecules in the interstitial space, and distribute into neutral lipids or phospholipids in the cellular space, while other effects are considered negligible.…”

Section: Very Weak Bases Neutrals Acids and Type 2 Zwitterionsmentioning

confidence: 99%

“…The experimental determination of tissue affinities can be costly and time consuming, and requires a substantial amount of compound, which is rarely available during discovery and early candidate selection (12). As a solution to this problem Poulin and Theil proposed in their seminal papers (13,14) to a priori predict the tissue distribution of a drug based on mechanistic description of the underlying physiology and the properties of drugs. Their key idea is to regard the most important tissue constituents-like water, neutral lipids, phospholipids, macro-molecules-and to predict the overall tissue distribution by means of the distribution into these tissue constituents.…”

Section: Introductionmentioning

confidence: 99%

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Physiologically based pharmacokinetic modelling: a sub-compartmentalized model of tissue distribution

Kleist

Huisinga²

2007

J Pharmacokinet Pharmacodyn

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We present a sub-compartmentalized model of drug distribution in tissue that extends existing approaches based on the well-stirred tissue model. It is specified in terms of differential equations that explicitly account for the drug concentration in erythrocytes, plasma, interstitial and cellular space. Assuming, in addition, steady state drug distribution and by lumping the different sub-compartments, established models to predict tissue-plasma partition coefficients can be derived in an intriguingly simple way. This direct link is exploited to explicitly construct and parameterize the sub-compartmentalized model for moderate to strong bases, acids, neutrals and zwitterions. The derivation highlights the contributions of the different tissue constituents and provides a simple and transparent framework for the construction of novel tissue distribution models.

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Section: Sub-compartment Tissue Distributionmentioning

confidence: 99%

Section: Sub-compartment Tissue Distributionmentioning

confidence: 99%

Section: Very Weak Bases Neutrals Acids and Type 2 Zwitterionsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Physiologically based pharmacokinetic modelling: a sub-compartmentalized model of tissue distribution

Kleist

Huisinga²

2007

J Pharmacokinet Pharmacodyn

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“…In the blood stream, a fraction of the drug dose can bind plasma proteins or erythrocytes and thus not be available for target tissue absorption, metabolism, or elimination [21][22][23]. Delivery through ingestion is complicated by the fact that the compound must be broken down and absorbed by the gastrointestinal tract before it enters circulation.…”

Section: Introductionmentioning

confidence: 99%

Biomedical Technologies for In Vitro Screening and Controlled Delivery of Neuroactive Compounds

Frampton¹,

Shuler²,

Shain³

et al. 2008

CNSAMC

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Cell culture models can provide information pertaining to the effective dose, toxiciology, and kinetics, for a variety of neuroactive compounds. However, many in vitro models fail to adequately predict how such compounds will perform in a living organism. At the systems level, interactions between organs can dramatically affect the properties of a compound by alteration of its biological activity or by elimination of it from the body. At the tissue level, interaction between cell types can alter the transport properties of a particular compound, or can buffer its effects on target cells by uptake, processing, or changes in chemical signaling between cells. In any given tissue, cells exist in a three-dimensional environment bounded on all sides by other cells and components of the extracellular matrix, providing kinetics that are dramatically different from the kinetics in traditional two-dimensional cell culture systems. Cell culture analogs are currently being developed to better model the complex transport and processing that occur prior to drug uptake in the CNS, and to predict blood-brain barrier permeability. These approaches utilize microfluidics, hydrogel matrices, and a variety of cell types (including lung epithelial cells, hepatocytes, adipocytes, glial cells, and neurons) to more accurately model drug transport and biological activity. Similar strategies are also being used to control both the spatial and temporal release of therapeutic compounds for targeted treatment of CNS disease.

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Physiologically Based Pharmacokinetic Modeling

Clewell

Reddy

Lavé

et al. 2010

Pharmaceutical Sciences Encyclopedia

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In the pharmaceutical area, the use of physiologically based pharmacokinetic (PBPK) models was limited in drug development due to the perceived mathematical complexity of the models and the labor‐intensive input data required. However, advances in the prediction of hepatic metabolism and tissue distribution from in vitro and in silico data have made the use of these models more attractive, providing the opportunity to gain mechanistic insight into the compound's properties. This article provides information necessary to understanding the application of PBPK models in preclinical drug development and advances in the available tools.

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Prediction of adipose tissue: Plasma partition coefficients for structurally unrelated drugs

Cited by 192 publications

References 41 publications

Physiologically based pharmacokinetic modelling: a sub-compartmentalized model of tissue distribution

Physiologically based pharmacokinetic modelling: a sub-compartmentalized model of tissue distribution

Biomedical Technologies for In Vitro Screening and Controlled Delivery of Neuroactive Compounds

Physiologically Based Pharmacokinetic Modeling

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